This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Graft versus Host Disease (GVHD) is a major cause of morbidity following allogeneic hematopoietic stem cell transplantation (HSCT). Current management of GVHD relies on global depletion or suppression of T cells, the cell type responsible for disease. However, allogeneic HSCT provides beneficial anti-tumor effects that are mediated by T cells. Greater understanding of the mechanisms involved in GVHD is necessary to prevent or minimize the disease without losing the associated graft-versus-tumor (GVT) activity of the graft. The role of interleukin-12 (IL-12) in GVHD has been studied and both positive and negative effects have been attributed to cytokine. Recent reports have shown that strategies that depleted IL-12 would have also depleted IL-23, a cytokine that shares a common p40 subunit with IL-12. I have found, using p40 deficient mice, that the combined loss of IL-12 and IL-23 ameliorations GVHD as would be expected. In striking contrast, loss of IL-12 alone (in IL-12 p35 deficient mice) exacerbates disease. This project will define the effects of IL-12 and IL-23 in murine bone marrow transplant models of acute GVHD and determine the mechanism(s) for the immunostimulatory and immunosuppressive activities of IL-12 and IL-23.
In specific aim 1, I will use mice that are disparate at both MHC major and minor antigens and available as IL-12 wild type, p40 deficient or IL-12 p35 deficient animals to characterize and quantify alloreactive T cell expansion, Th1/Th2 polarization and tissue-specific disease associated injury.
In specific aim 2, I will assess endogenous IL-12 and IL-23 for allogeneic anti-tumor effects and their association with GVHD in the murine models examined in specific aim 1. The overall goal is to determine if IL-12 and/or IL-23 are potential targets for therapeutic modulation to promote the anti-tumor activity of allogeneic hematopoietic stem cell transplants while diminishing the incidence or severity of GVHD.
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